tbuckley/cabot-search huggingface dataset:
Abstract 11598: <i>In Silico</i> Identification of Immunogenic Cardiac Troponin I Epitopes and Validation in Patients Treated With Immune Checkpoint Inhibitors
Authors: Shirley Xu, Peninah Pechenik, Sharma Kattel, Swati D Sonkawade, Sarmila Nepali, Fumito Ito, Umesh C Sharma, Saraswati Pokharel
Journal: Circulation (2022)

Introduction: Immune checkpoint inhibitors (ICIs) have contributed to the recent decline in death due to cancers like melanoma. However, serious cardiotoxic side effects (like fatal myocarditis) have been reported. Autoimmunity against cardiac proteins has been suspected but the underlying mechanism is not known. Hypothesis: ICI treatment induces the formation of autoantibodies against immunogenic sequences of cardiac troponin I (cTn I). Methods: We identified antigenic sequences in cardiac myosin and troponin I by bioinformatic analyses, including T- and B-cell epitope prediction methods. The sequences with the highest antigenicity scores were coated on plates for enzyme-linked immunosorbent assays (ELISAs). Sera from ICI-treated mouse models and patients were used as primary antibodies to detect self-reactivity against these peptides. Mice were treated every 3 days with a total of 17 doses of PD-1, CTLA-4, a combination of both, or isotype IgG control antibodies (Abs). For clinical samples, sera was taken from 26 ICI-treated patients with melanoma, including pre-treatment samples from 20 patients. Results: From the in silico analysis, we identified 5 cTn I and 2 myosin sequences as antigenic. Using ICI-treated mouse serum, we screened these peptides and found cross-reactivity with cTn I peptide T5, which reflects a flexible linker and portion of a helix in cTn I. After completing ICI treatment in mice, there was significant reactivity to T5 in combination treatment versus control (Absorbance: IgG 0.135±0.037, CTLA-4+PD-1 Abs 0.247±0.060, IgG vs. CTLA-4+PD-1 Abs p=0.02, n=5-9). There were also increased autoantibodies in combination treatment compared to CTLA-4 Abs (CTLA-4 Abs 0.123±0.040, CTLA-4 vs. CTLA-4+PD-1 Abs p=0.001, n=9-10). In our clinical studies, there was positive reactivity against peptide T5 of 6-7 fold change in 4 subjects (15% of patients) with late stage melanoma after the initiation of ICI therapy, as compared to the average pre-treatment value. Conclusions: Our study showed that ICI-therapy induced immune-reactive antibodies directed against antigenic targets of cTn I in both animal models and patients. These data suggest a novel mechanism of ICI-induced cardiotoxicity, which warrants further investigation.
Abstract 11285: Synthetic-Contrast-Enhanced Computed Tomography Creating by Machine Learning Without Contrast Media
Authors: Takanori Tsujimoto
Journal: Circulation (2022)

Introduction: Contrast-enhanced computed tomography (CECT) is the gold standard for the diagnosis of aortic dissection (AD), at the same time, CECT has risks of nephropathy and allergic reactions caused by contrast media. Hypothesis: Synthetic-contrast-enhanced computed tomography (SECT) created from non-contrast-enhanced computed tomography (NECT) by machine learning without contrast agents could be an alternative to CECT in the diagnosis of AD. Methods: 50 patients with type A AD and 200 patients without AD who underwent NECT and CECT in pairs at Kobe university hospital were randomly selected and used for model training and testing. 3120 CT slices were used for training and 379 slices were used for testing. AD detection algorithms for NECT or CECT were developed by convolutional neural networks using NECT datasets or CECT datasets respectively. A SECT creating algorithm was developed by u-net using the pairs of CT datasets. To provide visual explanations of diagnosis, the gradient-weighted class activation mapping (Grad-CAM) method was adapted. Results: The provided sensitivities of AD detection algorithms for NECT or SECT were 90 % and 97 %, and the specificities were 100 % and 100 % respectively. When the developed AD detection algorithms for CECT were adapted to SECT, the provided sensitivity of 100 %, and sensitivity of 95 %. Most slices SECT of patients with AD demonstrated intimal flap and/or thrombosed false lumen as the almost same as CECT. The Grad-CAM visualization revealed that the AD detection algorithm using SECT images identified intimal flap or thrombosed false lumen in images more clearly than the AD detection algorithm using NECT images. Conclusions: The SECT creating algorithm improved diagnostic sensitivity for detecting AD using NECT datasets, which suggests the potential of the proposed method to support the clinical practice by reducing complications of contrast agents.
Abstract 12930: Plasma Proteome Distinguishes Adaptive and Maladaptive Signaling in Repaired Tetralogy of Fallot
Authors: Andrea L Jones, Katie L Clouthier, Jonathan J Edwards, Anh Duc Mai, Hossein Fazelinia, Sushma Reddy, Laura M Mercer-Rosa
Journal: Circulation (2022)

Introduction: Patients who have undergone tetralogy of Fallot (TOF) repair are subject to chronic volume and/or pressure overload, leading to a 40% probability of right ventricular (RV) failure by the third decade of life. We sought to identify a plasma proteome profile of the systemic response to right heart stress to better understand the mechanisms of RV failure and identify novel RV remodeling biomarkers. Methods: Patients with repaired TOF were recruited at the time of standard of care cardiac MRI (CMR) (N=14), and blood samples were collected. Plasma proteomics was assessed using data independent acquisition mass spectrometry. Proteins that were significantly affected between groups were identified and used for pathway enrichment analysis. Results: Patients underwent primary TOF repair at median 2.9m (IQR 0.8, 4.1) and CMR at median 16yrs (IQR 15, 18). Patients were grouped based on median indexed RV end diastolic volume (RVEDVi). Group 1: median RVEDVi 146ml/m 2 (IQR 139, 164) (N=9); Group 2: median RVEDVi 114ml/m 2 (IQR 104, 130) (N=5); p&lt;0.001. RV ejection fraction was equal between groups (mean 56% vs. 55%; p=0.68). Forty-one proteins were significantly differentially abundant: 19 enriched in Group 1 and 22 enriched in Group 2 (Fig 1; p&lt;0.05). Adaptive signaling in Group 1 was characterized by upregulation of proteins involved in antioxidant mechanisms (SOD1, TXN, PRDX1&amp;2), calcium handling (S100A6, CALM1), and proteostasis (UBB, HSPA8). Maladaptive signaling was characterized by upregulation of glycolytic pathways (MDH1, PGK1) and heme protein oxidation (ALAD) and downregulation of proteins to counter acute stress (complements, ORM1&amp;2). Conclusion: Patients with repaired TOF and moderate-severe RV dilation have a distinct maladaptive plasma proteomic profile independent of ejection fraction. These data suggest that profiling the circulating plasma proteome may be used to monitor disease progression prior to the onset of clinical heart failure.
Abstract 11145: Biomechanical Engineering Analysis of Leaflet Kinematics and Native Coronary Flow After Valve-Sparing Aortic Root Replacement Using Four Graft Configurations
Authors: Yuanjia Zhu, Pearly K Pandya, Matthew H Park, Danielle Mullis, Robert Wilkerson, Abakar Baraka, Charles J Stark, Catherine A Wu, Hyunchel Joo, Y. Joseph J Woo
Journal: Circulation (2022)

Introduction: Different ex vivo root biomechanics after valve-sparing aortic root replacement (VSARR) using several graft configurations have been described. The impact of graft choice on each cusp’s kinematics and native coronary flow remains unclear. The objective was to analyze valve kinematics and coronary flow after VSARR using 4 graft configurations in a 3D-printed heart simulator ( Fig A ).[YZ1] Methods: Porcine aortic roots with coronary arteries were explanted (n = 5). Native roots served as controls ( Fig B ). Each sample underwent VSARR using straight graft (SG), Valsalva graft (VG), anti-commissural plication (ACP), and Stanford modification (SMOD) in a random order ( Fig C-G ). Hemodynamics and videometric data were analyzed ( Fig H, I ). Results: SG showed the lowest regurgitant fraction (2.8 ± 1.5 %) compared to control (6.3 ± 3.9 %, p = .0002), VG (12.2 ± 3.6 %, p = .002), ACP (12.9 ± 1.3 %, p = .001), and SMOD (12.2 ± 3.0 %, p = .001, Fig J, K ). The left coronary artery flow was higher in SG (0.68 ± 0.16 L/min) compared to VG (0.55 ± 0.22 L/min, p = 0.05) and SMOD (0.51 ± 0.23 L/min, p = 0.05, Fig L ). The right coronary artery flow was higher in SG (0.20 ± 0.10 L/min) compared to VG (0.07 ± 0.04 L/min, p = 0.04) and SMOD (0.08 ± 0.05 L/min, p = 0.04, Fig M ). SG (26.5 ± 17.6 cm/s) compared to VG (48.3 ± 19.0 cm/s, p = .001) and SMOD (39.5 ± 10.1 cm/s, p = .05) showed lower rapid opening velocity in the left coronary cusp (LCC). SG (8.1 ± 6.2 cm/s) compared to VG (15.0 ± 10.6 cm/s, p = .04) showed lower rapid closing velocity in the right coronary cusp. The VG (17.7 ± 9.7 Hz) had higher flutter frequency in the LCC compared to control (11.9 ± 4.1 Hz, p = .02). The SG (11.9 ± 4.5 dB/Hz) compared to ACP (16.4 ± 4.7 dB/Hz, p = .01) showed lower flutter power in the LCC. Conclusions: Compared to other configurations, SG had the most optimal hemodynamics, native coronary flow, and leaflet kinematics. Further in vivo validation studies should be performed to evaluate flow dynamics in the root and assess for clinical applicability.
Abstract 11284: Predicting Thermal Injury by Machine Learning Analysis of Luminal Esophageal Temperature Patterns in Atrial Fibrillation Ablation
Authors: Yaacoub Chahine, Tanzina Afroze, Savannah Bifulco, Fima Macheret, Mahbod Jafarvand, Patrick M Boyle, Nazem W Akoum
Journal: Circulation (2022)

Introduction: Luminal esophageal temperature (LET) monitoring during catheter ablation for atrial fibrillation (AF) is widely used to reduce the incidence of esophageal thermal injury (ETI). We sought to assess whether specific patterns of LET variation are associated with ETI. Methods: The CIRCA-S multi-sensor probe was used to record LET in AF patients undergoing radiofrequency (RFA) or cryoballoon ablation (CBA) ( Fig A ). Patients underwent upper endoscopy one day after ablation. LET data was analyzed for patterns associated with ETI ( Fig B ). A random forest classifier with 5x stratified cross validation was trained to predict ETI, and SHapley Additive exPlanations (SHAP) analysis was used to assess feature importance in the prediction of ETI. Results: A total of 90 patients (63% paroxysmal AF; 27% female) were included. Among them, 68 patients underwent RFA, and 22 patients CBA. ETI was detected in 11 patients (10 RFA and 1 CBA). In case of RFA, the highest LET recorded was similar between patients who had an ETI and those who did not (40.4 [39.1, 41] vs 40.6 [40.1, 41], p=0.4); however, the rate of LET rise for the highest recorded peak was higher (0.08 [0.03, 0.12] vs 0.02 [0.01, 0.05]; p=0.02) and area under the curve (AUC) for highest peak was smaller (412.5 [206.8, 634.1] vs 545.5 [369.9, 855.1]; p=0.066) in patients who had ETI. In case of CBA, the patient with ETI had a faster LET decline (0.12 vs 0.07 [0.02, 0.14]), and a smaller AUC for the lowest trough (2491.3 vs 2629.3 [1712.6, 5283.2]) compared to patients who had no ETI. SHAP analysis revealed that for the overall population, rate of LET change was the most important feature in the prediction of ETI ( Fig C ), and that a rate of LET change &gt;0.1°C/s is most predictive of ETI ( Fig D ). Conclusion: Rate of LET change and AUC for the recorded temperature are more important predictors of ETI compared to absolute peak temperatures. Prospective studies guided by these parameters are needed to demonstrate their efficacy in reducing ETI.
Abstract 12279: Cardiovascular Disease Progression in Children With Homozygous Familial Hypercholesterolemia Despite Early Diagnosis on a Genetic Cascade Screening Program
Authors: Fabiana C Juliani, Ana Paula M Chacra, Marcio H Miname, Wilson Salgado Filho, Marjorie H Mizuta, Cinthia E Jannes, Jose E Krieger, Raul C Maranhao, Raul D Santos, Viviane Z Rocha
Journal: Circulation (2022)

Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-c) and very high risk of premature atherosclerotic cardiovascular (ASCVD) and aortic/supraortic valve heart diseases (VHD). The study aim was to examine clinical and biochemical trajectories of a cohort of HoFH patients since childhood. Methods: In this longitudinal study we assessed the incidence of manifest or subclinical ASCVD (coronary or carotid) and VHD as well as plasma lipids in a cohort of HoFH subjects during a 12.9 ± 9.6 years follow-up. Results: From the 868 individuals ≤19 y-old (at baseline) that were genotyped on a genetic cascade screening program, 420 (48.4%) had an FH mutation. From children bearing mutations, 12 were true homozygotes and 1 was compound heterozygote (53.8% females, mean age 7.5 ± 4.1 years at the first visit). During follow-up all were on statin and ezetimibe therapies, and the mean final dose of atorvastatin was 56 ± 27 mg/d (n=10); and rosuvastatin, 26 ± 17 mg/d (n=3). Initial and on treatment LDL-c were 655 ± 177 mg/dL and 399 ± 150 mg/dL, respectively, with a mean 39.1% reduction (-256 mg/dL). None were under LDL apheresis; 2 patients used mipomersen, 2 lomitapide, and 2 are currently using PCSK9 inhibitors. Subclinical cardiovascular disease, either coronary, carotid or in aortic valve, was identified in 38.5% (n=5; mean age 16.4 ± 9.8 years), whereas 30.8% had a clinical cardiovascular event (n=4; mean age 22.8 ± 6.8 years), with 2 deaths. Therefore, 69.3% had either subclinical or manifest cardiovascular disease. Conclusion: Despite early diagnosis and LDL-c reduction HoFH is still marked by an adverse and premature cardiovascular disease progression. Conventional lipid lowering therapies are not adequate to prevent ASCVD and VHD disease course.
Abstract 13924: Impact of a Pandemic on Women Diagnosed With Peripartum Cardiomyopathy
Authors: Omar K Shahin, Hania N Shahin, Heineke S Hyunju, Mimi S Biswas
Journal: Circulation (2022)

Background: Peripartum cardiomyopathy (PPCM) is a dilated form of cardiomyopathy that occurs during the last month of pregnancy or up to five months postpartum. Approximately 1,100 women develop PPCM in the United States each year. The aim of our study is to compare the incidence of PPCM prior to the start of the Coronavirus Disease 2019 (COVID) pandemic to afterwards and to determine the impact of COVID on hospitalized patients with PPCM. Methods: This was a retrospective study of 2,286 patients with a diagnosis of PPCM who were admitted to a private hospital system across the United States between the year 2017 and year 2021. There was 1,790 patients in the pre-COVID cohort, and 496 patients in the COVID era cohort. Demographics of patients were collected, with t-test and chi square p-values utilization for statistical description. Results: The mean age of women was 32.13 years. In the COVID era cohort, the percentage of Hispanic patients was significantly higher than the pre-COVID era (16.84% vs. 12.34%, p=0.012). In the COVID era, patients were more likely to have preeclampsia (20.16% vs. 13.52%, p&lt;0.001), HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome (2.62% vs. 0.61%, p&lt;0.001), respiratory failure (19.56% vs. 10.57%, p&lt;0.001), and myocardial infarction (3.63% vs. 1.90%, p=0.022). There was no significant difference in troponin and d-dimer values between the two era cohorts. The average length of stay, percentage of patients admitted to the intensive care unit (ICU), and death did not significantly differ between the pre-COVID and COVID era cohorts. Conclusion: In our study, although there was no significant difference in length of stay, ICU admission, or death in the COVID era cohort, myocardial infarction, preeclampsia, HELLP syndrome, and respiratory failure were each more prevalent in women with PPCM during the COVID era. These findings might indicate suboptimal access to outpatient and inpatient medical care during the COVID pandemic, which could have led to these more serious diagnoses.
Abstract 12000: Ventricular Arrhythmias and Sudden Death Events Following Acalabrutinib Therapy Initiation for Hematology Malignancies
Authors: John Gambril, Seema A Bhat, Leylah Azali, Sunnia Chen, Lindsay Rosen, Marilly Palettas, Tracy Wiczer, Sujay Kalathoor, Qiuhong Zhao, Kerry Rogers, Adam Kittai, Michael Grever, Farrukh Awan, Patrick Ruz, John C Byrd, Jennifer Woyach, Daniel Addison
Journal: Circulation (2022)

Introduction: Acalabrutinib, a next generation Bruton’s tyrosine kinase inhibitor (BTKi) associates with dramatic efficacy against hematology malignancies. Unexplained ventricular arrhythmias (VAs) with next generation BTKi therapy have been reported. Yet, whether acalabrutinib associates with VAs in long-term follow up is unknown. Methods: Leveraging a cohort of 290 consecutive hematologic malignancy patients treated with acalabrutinib (2014-2020), we assessed VA incidence. The primary endpoint was incident VA development (ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular contractions). Probability Scores determined likelihood of acalabrutinib association. Incident rates as function of time on therapy were calculated. Weighted average incidence rates were compared to observed rates in a large contemporary similar aged general population using relative risk. Absolute excess risk (AER) for acalabrutinib associated VAs was estimated. Results: Over 1,063 person years of follow up, there were 8 incident VA cases, including 6 in those without coronary disease (CAD) or heart failure (HF), and 1 sudden death; median time to event was 14.9 months. Among those without prior ibrutinib use, CAD, or HF, weighted average incidence was 394 per 100,000 person years. This compares to 596 for ibrutinib related VAs (RR 0.66, P&lt;0.01; figure) and 48.1 among similar aged non-BTKi treated subjects (RR 8.2, P&lt;0.001; AER 346). Outside of age, no cardiac or electrocardiographic variables associated with VA development . Conclusions: Acalabrutinib associates with increased risk of incident VAs. Collectively, these data suggest VAs may be a class effect of BTKi therapies. Figure: Ventricular arrhythmia (VA) crude (A) and cumulative (B) incidence rates in acalabrutinib users versus ibrutinib and non BTKi treated populations. *Those without prior ibrutinib use or structural heart disease. **Assumes linear a event rate over time.
Abstract 13609: Heterogeneous Populations of Cytotoxic CD4 T Cells Are Expanded in Atherosclerotic Plaques of Patients With Type 2 Diabetes
Authors: Dayasagar Das, Ravneet Kaur, Michael Gildea, Natalia Eberhardt, Dawn Fernandez, Letizia Amadori, swathy sajja, Roza Shamailova, Ira J Goldberg, Thomas Maldonado, Caron Rockman, Chiara Giannarelli, Jeffrey Berger, Edward Fisher
Journal: Circulation (2022)

Introduction: Atherosclerotic cardiovascular disease (ACVD) is the main cause of morbidity and mortality in patients with type 2 diabetes (T2D). ACVD is more severe and diffuse in T2D than in subjects with no diabetes (ND). Moreover, cholesterol reduction in T2D leads to less plaques resolution. While the role of macrophages in T2D plaque pathology has been investigated, no studies have systematically investigated the heterogeneity of CD4 T cells in human plaques. Hypothesis: Plaques of patients with T2D have a greater CD4 T cell heterogeneity and pathogenic phenotypes compared with plaques of ND subjects. Methods: To identify the specific T cell alterations in plaques we analyzed scRNA sequencing data of &gt;80,000 plaque immune cells from 22 patients undergoing carotid endarterectomy with or without T2D (54.5% T2D). Results: Unbiased clustering of CD45+ cells identified a total of 24 immune cell clusters, including CD4 T cells that presented similar cell frequencies between T2D (~11%) and ND patients (~10%). CD4 T cells comprise 7 clusters: naïve, proliferating, central memory (CM), effector memory (EM), T regulatory (Tregs), cytotoxic (CTL), and gamma delta (γδ) T cells. CD4 CTLs expressed GZMB, GNLY, PRF1 , and could be divided into TRAC +EM (cluster 9) and CTLγδ T cells expressing both TRDC and TRGC2 (cluster 5). CTLγδ T cells were significantly expanded in T2D plaques (p=0.032), and expressed high levels of GZMA and transcription factors involved in T cell differentiation such as RUNX and TBX21 . These CTLγδ T cells are enriched with sets of genes involved in T-cell activation, numerous pathways of apoptosis, cytotoxicity, chemotaxis and cytokine signaling (i.e. IL1, IL2, IL9 ). Conclusions: Our data show that plaques from patients with T2D are highly enriched in unique CTL/γδ T cells and suggest that their cytotoxic potential may contribute to the increased cardiovascular risk of subjects with T2D.
Abstract 12849: Impact of Age on Exercise Capacity After Home-Based Cardiac Rehabilitation During the Covid-19 Pandemic
Authors: Tomoaki Hama, Audry Chacin Suarez, Thomas G Bissen, Thomas P Olson
Journal: Circulation (2022)

Introduction: The COVID-19 pandemic resulted in the closure of many center-based cardiac rehabilitation programs leading many institutions to rely on home-based cardiac rehabilitation (HBCR) to provide critical secondary cardiovascular disease prevention and rehabilitation. The impact of age on the change of exercise frequency and exercise capacity as a result of HBCR during the COVID-19 pandemic remains unknown. Methods: Retrospective cohort study of 567 HBCR patients between March 2020 and May 2021. Patients who completed the Duke Activity Status Index questionnaire at enrollment and completion of HBCR were included. We calculated the number of reported exercise days/week , exercise min/day, and VO 2 peak estimated. Patients were divided into two groups according to age (Younger&lt;65 y.o; Older≥65 y.o). Continuous data are described as mean ±SD and baseline data compared with a two-sample t-test. The delta change from pre-post between groups also are compared with a two-sample t-test. Results: Of 567 HBCR patients, 118 patients completed both pre and post HBCR questionnaires (Younger, n=54, 56±8 years old vs Older, n=64, 74±7 y.o, p&lt;0.05). Both groups improved exercise days/week (4.4±2.8 to 5.8±1.3 vs 3.8±2.9 to 5.6±1.6 days, p&lt;0.05 for both), exercise min/day (21±20 to 41±17 vs 20±20 to 37±17 min, p&lt;0.05 for both), and VO 2 peak (20.5±7.1 to 27.6±8.0 vs 21.9±8.1 to 25.1±7.7 ml/min/kg, p&lt;0.05 for both). The delta change for exercise days/week and exercise min/day were not significantly different between groups (1.4±2.7 vs 1.9±2.7 days and 19±19 vs 17±18 min, p&gt;0.05); however, the Younger patients significantly increased their VO 2 peak more than the older patients (7.1±6.1 vs 3.2±5.3 ml/min/kg, p&lt;0.05). Conclusions: During the COVID-19 pandemic, exercise frequency (days/week and min/day) and exercise capacity (estimated VO2peak) increased in all patients participating in HBCR. With this, the increase in estimated exercise capacity was greater in younger patients compared with older patients. These findings suggest that additional work is needed to explore factors potentially limiting improvement and strategies to maximize improvement in exercise capacity in older patients participating in HBCR.